The present invention relates to a method for treating central nervous system and peripheral nervous system cholinergic deficit states. It also relates to novel compositions of matter for treating such disease states. More particularly, the present invention relates to the use of monoamine acridine derivatives in the treatment of such states.
A wide variety of recognized diseases fall within the ambit of cholinergic deficit states. At the present time, Alzheimer's disease has gained the most attention. In 1907 Alois Alzheimer described a 51 year-old woman with a progressive dementia leading to death within approximately four and one-half years. At autopsy, the woman's brain was grossly atrophic. Microscopic examination of the brain revealed diffuse neurofibrillary degenerative change with numerous miliary foci (senile plaque). The dementia described has been given several names, including Alzheimer's disease, Senile Dementia of the Alzheimer's type, PreSenile Dementia and Primary Degenerative Dementia. It is now recognized as one of our major health care problems. The disease is a progressive deterioration of the brain resulting in memory loss, cognitive deficits, and altered behavior. The prevalence of the disease is not clearly established and estimates vary from 10 to 15 percent of the population over age 65. The major brunt of the disease is in the eighth and ninth decades, and this is the segment of the population increasing most rapidly in number. Alzheimer's disease is estimated to affect 1.5 to 3.0 million people in the United States alone at the present time. Thus, Alzheimer's disease is a major health problem and is reported to be the fifth most common cause of death in the United States. With advances in medical care, the survival rate of patients with dementia has been increasing. So the increaase in the size of the at risk population and its survival makes the search for solutions a high priority. In addition, the cost of nursing home rates alone is staggering.
It is now recognized that Alzheimer's disease may occur at virtually any age. The precise cause of the illness is unknown. A variety of non-specific treatments have been proposed which rely on the theory that the cause of the disease is cerebral atherosclerosis. Such treatments include the use of cerebral vasodilators, vitamins, chelating agents, hyperbaric oxygen, precursor amino acids and vasopressin. However, there is no convincing evidence that any of the foregoing are beneficial.
In 1976, the neurochemical deficit of Alzheimer's Disease became partially defined by Davies et al, "Selective Loss of Central Cholinergic Neurons in Alzheimer's Disease", Lancet (1980), vol. 2, p. 1403. Numerous investigators have demonstrated a reduction in the enzyme choline acetyltransferase in autopsy material from Alzheimer's patients versus agematched controls. It has been determined that there is an additional moderate reduction of both true and "pseudo" acetylcholinesterase (AChE and BuChE). Post synaptic muscarinic receptors are generally intact. In addition, direct correlation of memory deficits seen in Alzheimer's disease patients to the post-mortem choline acetyltransferase levels has been established. Recent evidence suggests that the most important specific locus of cholinergic neurons in the central nervous system of patients with Alzheimer's disease is the nucleus basalis and the diagonal band of Broca.
At the present time, there are three possible approaches to enhance cholinergic transmission in the central nervous system. The first approach is to enhance cholinergic neurons by excessive exposure to a form of choline. Such attempts have been mildly successful but only in the early stages of Alzheimer's disease.
The second approach involves post synaptic direct stimulation of muscarinic receptors by oral or intravenous administration of drugs. No reports of this approach appear in the literature. This is likely because such direct stimulation by agents such as oxotremorine, muscarine and pilocarpine would be expected to have a low therapeutic index, i.e., a high effective dose to toxic dose ratio. In addition, a variety of undesirable, non-specific side efects would be expected. One agent, bethanechol chloride, a post synaptic, muscarinic agonist has been administered intrathecally with limited success on four patients by Harbaugh, R. E. et al and reported in "Preliminary Report: Intracranial Cholinergic Drug Infusion in Patients with Alzheimer's Disease", Neurosurgery (1984), vol. 15, pp. 514-518. This method of administration was fraught with problems since it requires the heroics of neurosurgery. Further, bethanechol chloride itself is not the ideal agent since it is a quaternary ammonium compound and thus has limited penetration of the blood-brain barrier.
The third approach to enhance cholinergic transmission involves the inhibition of acetylcholinesterase, the enzyme that metabolizes acetylcholine. In this approach a reversible carbamate inhibitor such as physostigmine may be used. The most obvious disadvantage associated with this approach is that the short half-life of these drugs requires a frequency of administration of approximately every two to four hours as noted by Thal, L. J. et al, "Oral Physostigmine and Lecithin Improve Memory in Alzheimer's Disease", Annals of Neurology (1983), vol. 13, no. 5, pp. 491-496. The reversible carbamate inhibitors also have a low therapeutic index. Thus, even the inhibition of acetylcholinesterase does not appear to offer a practical solution for chronic cholinergic deficit states such as Alzheimer's disease.
Yet another class of pharmacological agents exist which enhance the cholinergic system through synaptic inhibition of acetylcholinesterase. One member of this claim is 1,2,3,4-tetrahydro-5-aminoacridine (THA), reported by Summers, W. K. et al, "THA--A Review of the Literature and Its Use in Treatment of Five Overdose Patients", Clinical Toxicology (1980), vol. 16, pp. 269-281. When 1,2,3,4-tetrahydro-5-aminoacridine was first explored in the late 1940's, it was determined that it was a potent anticholinesterase that reversed morphine narcosis, reversed barbiturate narcosis, reversed magnesium chloride induced coma, and prevented ventricular fibrillation precipitated by digitalis or electric shock.
In 1979 the use of intravenous 1,2,3,4-tetrahydro-5-aminoacridine on patients with Alzheimer's disease was reported by Summers, W. K. et al, "Use of THA in Treatment of Alzheimer-Like Dementia: Pilot Study in Twelve Patients", Biological Psychiatry (1981), vol. 16, no. 2, pp. 145-153. This study tested the cholinergic hypothesis of organic brain syndromes, in general, and of Alzheimer's disease, in particular. Approximately 75% of the patients showed improvement in the global sense. However, in practical terms, this study did not provide a treatment for Alzheimer's disease. Giving medications acutely (suddenly not chronically) and intravenously is not a solution for a chronic disorder such as Alzheimer's disease which oftentimes follows a course of eight years from onset to death.
Kaye, W. H. et al, "Modest Facilitation of Memory in Dementia with Combined Lecithin and Anticholinerestase Treatment", Biological Psychiatry (1982), vol. 17, no. 2, pp. 275-280 reported that only a modest improvement in memory could be obtained by use of oral 1,2,3,4-tetrahydro-5-aminoacridine. Kaye et al tested the use of 30 mg of 1,2,3,4-tetrahydro-5-aminoacridine (THA) and/or 60 grams of lecithin on ten patients. Both the 30 mg of THA and the 60 grams of lecithin were divided into three doses and administered to each patient at 10:00 pm and then the next day at 8:00 am and noon. The patients were then tested at 2:00 pm. Four trials of drug administration were conducted on each patient. A minimum of 56 hours elapsed between trials. The four trials involved both lecithin placebo and THA placebo; active lecithin and lecithin placebo; and active THA and active lecithin. No dosage variation was tested. The results of the study were not promising. Although the less impaired patients increased the number of words remembered on serial learning testing with the combined 1,2,3,4-tetrahydro-5-aminoacridine/lecithin therapy, the combined therapy did not restore any patient to normal functioning. Neither lecithin nor 1,2,3,4-tetrahydro-5-aminoacridine alone produced improvement in memory function in any of the patients. Thus, researchers in this field turned their attention to other treatment methods as evidenced by Harbaugh, R. E. et al, noted above, and Thal, L. J. et al, noted above.
Earlier work in this field also demonstrated that 4-aminopyridine was capable of reversing certain central anticholinergic states such as drug-induced coma. The mechanism of 4-aminopyridine is now believed to be due to post synaptic potassium channel blockade as described by Soni, N. et al, "4-Aminopyridine--A Review", Anesthesia and Intensive Care (1982), vol. 10, pp. 120-126. Thus, the search for a suitable treatment for Alzheimer's disease continues.